What is the alternative treatment regimen for gout when allopurinol (xanthine oxidase inhibitor) is not effective?

Alternative Treatment Regimen When Allopurinol Fails in Gout

When allopurinol is not working, switch to febuxostat as the preferred first-line alternative xanthine oxidase inhibitor, starting at 40 mg daily and titrating to 80 mg daily after 2 weeks if serum uric acid remains above 6 mg/dL. 1, 2

Initial Assessment: Define "Not Working"

Before switching therapy, verify that allopurinol has truly failed by confirming:

• Adequate dosing: Allopurinol should be titrated up to 800 mg/day (the maximum FDA-approved dose) if needed to reach target serum uric acid <6 mg/dL 1
• Sufficient duration: Allow at least 2-4 weeks between dose escalations 1
• True intolerance vs. inadequate trial: Many patients are kept on subtherapeutic doses (≤300 mg/day) when higher doses are both safe and necessary 1

First-Line Alternative: Febuxostat

Febuxostat is the most effective alternative when allopurinol cannot be used or has failed at maximum tolerated doses. 2, 3

Dosing Strategy

• Start at 40 mg once daily 1, 4
• Increase to 80 mg once daily after 2 weeks if serum uric acid remains ≥6 mg/dL 4, 5
• No dose adjustment needed in mild-to-moderate renal impairment (eGFR ≥30 mL/min), which is a major advantage over allopurinol 2, 6, 5

Efficacy Evidence

• Febuxostat 80 mg achieves target serum uric acid <6 mg/dL in 53-62% of patients compared to only 21% with allopurinol 300 mg 7, 8
• Mean reduction in serum uric acid is -2.92 mg/dL (-27%) with febuxostat vs. -2.41 mg/dL (-24%) with allopurinol 8
• Patients reach target serum uric acid faster with febuxostat (86 days vs. 99 days) 8

Critical Cardiovascular Warning

If the patient has established cardiovascular disease or experiences a new cardiovascular event while on febuxostat, conditionally recommend switching to an alternative urate-lowering therapy due to FDA black box warning regarding cardiovascular risk. 1, 2, 6

Second-Line Alternatives: Uricosuric Agents

If febuxostat cannot be used or fails, consider uricosuric agents based on renal function:

For Normal Renal Function (eGFR ≥60 mL/min)

• Probenecid: Start 500 mg once or twice daily, titrate to 1-2 g/day 1, 2
  • Contraindicated in urolithiasis due to increased kidney stone risk 2, 3
• Sulphinpyrazone: 400 mg/day (where available) 2, 3

For Mild-to-Moderate Renal Impairment (eGFR 30-59 mL/min)

• Benzbromarone: Can be used without dose adjustment 1, 2, 6
  • Carries small risk of hepatotoxicity requiring monitoring 2
  • Not available in the United States

Combination Therapy Strategy

For patients with severe tophaceous gout not achieving target on monotherapy, combine a xanthine oxidase inhibitor (febuxostat) with a uricosuric agent (probenecid or benzbromarone). 1, 2

• The 2016 EULAR guidelines support this approach when monotherapy fails to achieve serum uric acid targets 1
• The 2020 ACR guidelines conditionally recommend switching to an alternate xanthine oxidase inhibitor over adding a uricosuric when the first xanthine oxidase inhibitor fails 1

Mandatory Flare Prophylaxis

Always initiate anti-inflammatory prophylaxis when starting or switching urate-lowering therapy:

• Colchicine 0.5-1 mg daily is the preferred prophylactic agent 1, 2
  • Reduce dose to 0.5 mg daily in renal impairment 1, 6
• Alternative options: Low-dose NSAIDs or prednisone/prednisolone 5-10 mg daily 1
• Continue prophylaxis for 3-6 months minimum, or longer if flares persist 1, 2

Treatment Targets and Monitoring

Target serum uric acid <6 mg/dL for all patients; consider <5 mg/dL for severe tophaceous gout until tophi resolve. 1, 2, 6

• Monitor serum uric acid every 2-5 weeks during dose titration 1, 6
• Once at target, monitor every 6 months 1
• Never allow serum uric acid to remain <3 mg/dL long-term 1

Last Resort: Pegloticase

For patients with severe debilitating chronic tophaceous gout who have failed all oral urate-lowering therapies at maximum doses, pegloticase is indicated. 1, 9

• Dose: 8 mg IV every 2 weeks 9
• Strongly recommended against as first-line therapy due to cost, safety concerns, and risk of anaphylaxis 1
• Requires premedication with antihistamines and corticosteroids 9
• Monitor serum uric acid before each infusion; consider discontinuing if levels rise above 6 mg/dL on two consecutive measurements 9

Essential Adjunctive Measures

Implement lifestyle modifications concurrently with any pharmacologic change:

• Weight loss if overweight 1, 6
• Limit alcohol (especially beer and spirits) 1, 6
• Avoid sugar-sweetened drinks and high-fructose corn syrup 1, 6
• Reduce purine-rich foods (meat, seafood) 1, 6
• Discontinue diuretics if possible; consider losartan for hypertension or fenofibrate for dyslipidemia 1, 6

Common Pitfalls to Avoid

• Do not abandon allopurinol prematurely: Many patients can tolerate doses >300 mg/day with proper titration 1
• Do not start urate-lowering therapy without flare prophylaxis: This guarantees acute flares and poor adherence 1
• Do not use febuxostat as first-line in patients with cardiovascular disease: Start with properly dosed allopurinol first 1, 2
• Do not use probenecid in patients with kidney stones or renal impairment: It will worsen both conditions 2, 3